High-fat diet disrupts a septal control on feeding to promote obesity in male mice.

The global epidemic of diet-induced obesity poses a significant health challenge. Among brain regions regulating energy homeostasis, the lateral septum has emerged as a critical brake on feeding behavior to prevent overeating. However, the neural adaptations within the septal area under high-fat diet (HFD) and consequent contributions to obesity remain unknown. Utilizing high-throughput single-nucleus RNA sequencing, slice electrophysiology and in vivo calcium imaging, we identified HFD-induced alterations in the transcriptional profiles and neural activity within the septal area of male mice. The HFD suppresses septal neuronal activity by downregulating hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1), and weakens inhibitory control over downstream targets through reduced expression of glutamate decarboxylase 2 (Gad2). Overexpression of Hcn1 and Gad2 enhances septal neuronal activity, restores GABA levels, and prevents HFD-driven overeating and obesity. These findings illustrate how diet disrupts the brain's feeding suppression system, leading to overeating and obesity.